Project Summary My career goal is to become an independent investigator and educator who studies structure-function mechanisms of tendon aging and injury and how they may be improved using biomaterials. My research training in bioengineering started by studying the role of healing and fatigue loading on multiscale tendon properties. I realized that knowledge of biomaterials and therapeutic delivery strategies would be essential to develop treatments for tendon. During my F32 postdoctoral training, we have developed and explored the capacity of tough adhesive biomaterials, inspired by the mucus secreted by slugs, to adhere strongly to tendon surfaces. The goal of this tough adhesive biomaterial is to provide mechanical support and a template for tendon regeneration, serve as a depot for local delivery of agents, support cell growth and infiltration, and provide gliding of surrounding tissues. This K99/R00 Application examines a new cell delivery strategy to dynamically recruit cells in vivo, expand them, and release them on-demand to promote tendon healing using this biomaterial platform. My mentoring team consists of Dr. David Mooney (primary mentor) and seven other renowned scientists specializing in tendon developmental and aging biology, musculoskeletal biology, drug delivery, orthopaedic bioengineering, materials science, and orthopaedic surgery. They provide me with an exceptional environment to investigate these questions and develop the necessary skills to contribute to the field as an independent investigator. We hypothesize that this biomaterial system can be tuned to recruit, expand, and deliver tendon cells (using tough adhesive hydrogels) and augment tendon properties during aging and injury. This hypothesis will be tested with the following aims: (1) develop and examine the ability of tough hydrogels containing chemotactic agents to recruit tendon-derived cells, promote their proliferation, and increase expression of tendon markers throughout aging and injury in vitro and in vivo; (2) develop and examine the ability of hydrogel degradation and embedded fibers to template mature tendon, drive expression of tendon markers, and promote cell release from the scaffold to the injury site throughout aging and injury, in vitro and in vivo; and (3) investigate the ability of the tough adhesive hydrogel system to restore age-related deficits in tendon homeostasis and healing using a clinically-relevant Achilles tendon rodent model. Success would have a dramatic impact on individuals suffering from tendon dysfunction following injury and could contribute to the development of on-demand therapeutics for other musculoskeletal and connective tissue diseases. Overall, this comprehensive project and training plan will provide me outstanding training to develop the technical and professional skills necessary to establish a successful and independent research program to study and provide mentoring in musculoskeletal tissue aging and biomaterials.